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| Status |
Public on Jul 22, 2012 |
| Title |
Idh1-R132H mutation increases murine hematopoietic progenitors and alters epigenetics. |
| Organism |
Mus musculus |
| Experiment type |
Methylation profiling by high throughput sequencing
|
| Summary |
Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequent in human glioblastomas1 and cytogenetically normal acute myeloid leukemias (AML)2. These alterations are gain-of-function mutations in that they drive the synthesis of the “oncometabolite” R-2-hydroxyglutarate (2HG)3. It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukemogenesis. Here we report the characterization of conditional knock-in mice in which the most common IDH1 mutation, Idh1-R132H, is inserted into the endogenous murine Idh1 locus and is expressed in cells of the hematopoietic (Vav-KI) or more specifically in cells of the myeloid (LysM-KI) lineage. These mutants show increased numbers of early hematopoietic progenitors and develop splenomegaly and anemia with extramedullary hematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells exhibit both hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1/2-mutant AML. Thus, our study is the first to describe the generation of conditional Idh1-R132H-KI mice. Furthermore, our study is also the first report showing the induction of a leukemic DNA methylation signature in a modeled system and sheds light on the mechanistic links between IDH1 mutation and human AML.
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| Overall design |
DNA methylation profiling in LSK cells from IDH1-R132H knock-in mice vs. control mice
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| Contributor(s) |
Sasaki M, Knobbe CB, Mak T, Figueroa ME, Melnick A |
| Citation(s) |
22763442 |
| Submission date |
Jun 13, 2012 |
| Last update date |
May 15, 2019 |
| Contact name |
Maria Eugenia Figueroa |
| E-mail(s) |
mef162@miami.edu
|
| Organization name |
University of Miiami
|
| Department |
Human Genetics
|
| Lab |
Maria Figueroa
|
| Street address |
1501 NW 10th Ave, BRB 709A, Locator code C227
|
| City |
Miami |
| State/province |
FL |
| ZIP/Postal code |
33136 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
|
| Samples (5)
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| Relations |
| BioProject |
PRJNA168439 |
| SRA |
SRP013732 |
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